Single Compound Is Triple Threat among Neglected Tropical Diseases

EM image of the protozoan parasite (Trypanosoma brucei) that causes Africian sleeping sickness. [WikiCommons]

Parasitic infections from protozoan species affect hundreds of millions of individuals annually, mounting a massive death toll globally. Yet, among these diseases, there are a few that are isolated to much smaller regions and populations, causing them to be often overlooked during drug development.    

Now scientists at the Wellcome Trust, Novartis Research Foundation (GNF), Novartis Institute for Tropical Diseases (NITD), University of York, University of Washington, and the University of Glasgow have identified a chemical that can cure three of these neglected diseases in mice—Chagas disease, leishmaniasis, and human African trypanosomiasis (sleeping sickness). Additionally, the newly developed compound does not harm human cells in laboratory tests, providing a strong starting point for drug development.

“We found that these parasites harbor a common weakness,” explained senior study author Frantisek Supek, Ph.D., research investigator at GNF. “We hope to exploit this weakness to discover and develop a single class of drugs for all three diseases.”

Chagas disease, leishmaniasis, and human African trypanosomiasis affect 20 million people worldwide and lead to more than 50,000 deaths annually. These eukaryotic parasites—commonly referred to as kinetoplastids— share similar biology and genetics, which led the researchers to think it possible to find a single chemical that could destroy all three. The research team uncovered an enzyme common to all three parasites and developed a chemical that binds to the “target,” preventing it from functioning. 

As part of the research, three million compounds held in the Novartis chemical library were tested by a phenotypic screen against live parasites and the most active were then modified over 3000 times using synthetic chemistry before the most potent one was identified— a compound called GNF6702.

“It's a breakthrough in our understanding of the parasites that cause the three diseases, potentially allowing them to be cured,” noted co-author Jeremy Mottram, Ph.D., chair in pathogen biology at the Centre for Immunology and Infection within the University of York. “This early-phase drug discovery project will now move toward toxicity testing prior to human trials.”

The findings from this study were published recently in Nature in an article entitled “Proteasome Inhibition for Treatment of Leishmaniasis, Chagas Disease, and Sleeping Sickness.”

Much of the research was performed using in vivo imaging technology and initially focused on human African trypanosomiasis, a disease found in sub-Saharan Africa and transmitted by the tsetse fly. The disease gets its more common name from the disturbance of the sleep cycle caused by the protozoan parasites—Trypanosoma brucei—infecting the brain, causing victims to fall into a coma and die.

Finding a drug that can target the disease in the brain has always been a challenge for scientists, but the research team believes they have made a breakthrough using an animal model of the human disease.

“We were able to detect the parasite in the brain using an imaging system that detects the presence of genetically modified light-emitting parasites,” remarked co-author Elmarie Myburgh, Ph.D., postdoctoral fellow in the department of biology at the University of York. “We then tested the chemical developed by Novartis using our imaging method, which showed that it could get into the brain and kill the parasites.”

“It is a great example of collaboration between industry and academic partners,” Dr. Myburgh added. “By combining resources and expertise, you can really make significant scientific progress.”

Existing treatments for the three diseases are expensive, often have side effects, and are not very effective. The fact that GNF6702 does not seem to have any adverse effects in mice suggests that it might have fewer side effects than existing drugs, although this will need to be explored in human studies. GNF6702 is now being tested for toxicity before it can be moved into clinical trials.

“These three diseases lead to more than 50,000 deaths annually, yet they receive relatively little funding for research and drug development,” stated Stephen Caddick, Ph.D., director of innovation at the Wellcome Trust. “We hope that our early-stage support for this research will provide a basis for the development of new treatments that could reduce suffering for millions of people in the poorest regions of the world.”